4.20 - PGT

Question 1

Define mosaicism and distinguish it from chimerism

Answer 1

presence of two or more genetically different cell lines in an individual who has developed from a single zygote (fertilized egg)
*chimerism is a single organism composed of two or more genetically distinct cell lines that originated from different zygotes

Question 2

Explain how mosaicism can arise from meiotic errors. Discuss anaphase lag

Answer 2

• meiotic non disjunction, homologous chromosomes or sister chromatids fail to separate correctly, results in extra copy of 1 chromosome in egg, fert = 1 extra copy of chromosome in zygote (trisomy)
• trisomies of maternal origin 10x more common than paternal origin
  -anaphase lag - delayed movement of chromosome during anaphase so chromosome is excluded from nucleus when it reforms and is ultimately destroyed. –> corrects the trisomy, but results in mosaicism

Question 3

Explain how mosaicism can arise from mitotic errors

Answer 3

mitotic nondisjunction (sister chromatids fail to separate correctly) results in extra copy of 1 chromosome (trisomy) in daughter cell, then one with only 1 copy (monosomy) which is lethal

Question 4

Explain the consequences of mosaicism arising early (cleavage stage) versus late (blastocyst stage) in embryonic development. Indicate the potential fates of the different genetic lineages.

Answer 4

-if it happens early (cleavage stage) and the cell survives to reproduce, chromosomal mosaicism is more likely to be generalized and affect multiple types of cells
—> mosaicism of embryo and placenta
-if it happens later (blastocyst stage), it may only affect specific tissues
—-> mosaicism confined to the embryo, confined placental mosaicism, no chromosomal mosaicism

Question 5

Explain why the incidence of mosaicism decreases during embryonic and fetal development. What mechanisms can explain the observed decline in mosaicism?

Answer 5

i think cause embryo self - correction may occur. Euploid cells proliferate faster than aneuploid cells. also mosaic embryos may halt proliferation of abnormal cells or exclude abnormal cells

Question 6

Explain how NGS can be used to diagnose disorders.

Answer 6

NGS = next generation sequencing. sample undergoes fragmentation and sequencing to be compared to a reference genome to determine chromosomal copy number
- can detect 24 chromosome aneuploidy, mosaicism, triploidy

Question 7

Describe the arguments in favor of universal PGT

Answer 7

-decreased termination due to aneuploidy
-increased pregnancy rates
-reduced miscarriage rates

Question 8

Explain the general considerations for PGT (pre-implantation genetic testing)

Answer 8

1. genetic counseling must include discussion of alternate strategies such as donor gametes or adoption
2. diagnostic methodology may be expensive
3. Biopsy may damage embryo
4. Not all genetic abnormalities can be diagnosed
5. There may be no “unaffected” embryos to transfer
6. controversial applications (gender selection, savior siblings, designer babies)
7. misdiagnosis may result from mosaicism
8. Prenatal diagnosis (CVS or amniocentesis) is recommended for confirmation of PGS/PGD

Question 9

Answer 9

D - 47, XY, +18